Since the introduction of the concept of antibody-drug conjugates (ADCs) three decades ago, this area has been advanced greatly along with improved ADC and linker technology. The approved drugs Adcetris (Brentuximabvedotin) in 2011 and Kadcyla (Trastuzumabemtansine) in 2013 have dramatically increased the interests and efforts on ADC drug discovery and development all over pharmaceutical, biopharmaceutical and research institutions worldwide. Success ratios of ADC drugs in clinical trials are largely dependent on ADC biomolecules's efficacy and toxicity, especially when the free drugs could not be cleaved and released from the whole ADC molecules in biological system before reaching the targeted cancer cells. So far there are only three main families of cytotoxins successfully used for ADC drugs developed in clinical trials. Among them, auristatin, such as monomethylauristatin E (MMAE) derived from natural dolastatin 10 has been used for Adcetris, an approved drug for the treatment of Hodgkin lymphoma/ALCL non-Hodgkin lymphoma. MMAE is generally conjugated antibodies through a peptide-cleavable self-immolating linkage system. [Gail Lewis Phillips, Antibody-Drug conjugates and Immunotoxins, Humana Press, 2013]. Maytansinoids have been used for marketing Kadcyla for treatment of late stage Her2 positive breast. Auristatins and maytansinoids are microtubule-binding agents. The third one is calicheamicin, a DNA-damaging agent, which was also used for several ADCs developed in clinical trials. Some of the problems facing the first generation of ADCs are in employing ADCs bearing more highly potent agents. The use of ADCs bearing more highly potent effectors will increase the probability of delivering a therapeutic dose to tumors cells that have low antigen expression or have poor processing. The properties of high potency, stability in circulation, reasonable aqueous solubility, and efficient metabolite release in targeted cells will be highly important in designing new payloads for ADCs.
Thus, there remains a need to discover novel cytotoxins which show higher potency against cancer cells, but lower toxicity for normal cells. Our current disclosure addresses the invention of a novel family of dolastatin pentapeptide-like cytotoxins and biological results of the ADC molecules prepared thereof.